Functional Implications of Nav16

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These results demonstrate the co-expression of Nav1.6 and the Na/Ca exchanger at regions of axonal injury in EAE and in MS and provide, for the first time, information about the molecular identity of a sodium channel subtype that may drive reverse Na/Ca exchange in neuroinflammatory disorders. Physiological data are consistent with a contribution of Nav1.6 to neuronal injury. Rapidly inactivating sodium current would not be expected to produce the sustained influx of Na that is needed to drive reverse Na/Ca exchange. As described previously, a persistent sodium conductance has been shown to play a prominent role in the triggering of reverse Na/Ca exchange and resultant calcium entry in myelinated axons (Stys et al., 1992, 1993). Baker and Bostock (1997) demonstrated a TTX-sensitive, low-threshold persistent sodium current within large diameter dorsal root ganglion cells that gives rise to myelinated axons.

Nav1.6 is expressed at high levels within these neurons while they express Nav1.2 at only low levels (Black et al.,

1996). Nav1.6 is, moreover, known to produce a persistent sodium current that becomes larger with depolarization (see, for example, Smith et al., 1998; Raman and Bean, 1997; Tanaka et al., 1999). Herzog et al. (2003) performed patch clamp analysis on dorsal root ganglion neurons expressing Nav1.6 channels (using tetrodotoxin-resistant recombinant channels, permitting unequivocal identification of Nav1.6 current) and detected persistent Nav1.6 currents in all cells that they studied. Fig. 7 shows a persistent current produced by Nav1.6 when expressed within dorsal root ganglion neurons. Although Nav1.2 may produce a persistent current when co-expressed with G-protein Py subunits (Ma et al.,

1997), Nav1.6 channels produce a much larger persistent current than Nav1.2 (Smith et al., 1998), and in many cells types Nav1.6 is responsible for the majority of persistent current (Maurice et al., 2001).

Collaboration of Nav1.6 and the Na/Ca exchanger in triggering axonal degeneration would suggest that subtype-specific blockade of Nav1.6 (or, preferably, of the persistent component of the current produced by these channels) might have a protective effect, preventing axonal degeneration. The clinical efficacy of such an approach would depend, in part, on the proportion of Nav1.6 channels that would have to be blocked along demyelinated axons and on the safety factor (in terms of the fraction of Nav1.6 channels that are required to remain operable) at normal nodes where Nav1.6 is widely deployed. The development of Nav1.6-specific blockers may make it possible to test this hypothesis. Encouraging results have been provided by the demonstration that the nonspecific sodium channel blockers phenytoin (Lo et al., 2002, 2003) and flecainide (Bechtold et al., 2004) provide neuroprotection in EAE where they prevent axonal degeneration, maintain axonal conduction, and improve clinical outcome without apparent deleterious side effects in animal models.

Figure 7 Persistent current produced by Nav1.6. Sodium current elicited in a typical Nav1.8-null DRG neuron expressing Nav1.6r channels by a 500-ms ramp depolarization from -100 to +30 mV The peak sodium current amplitude elicited in this cell with step depolarizations was 65.1 nA. (From Herzog et al., 2003.)

Figure 7 Persistent current produced by Nav1.6. Sodium current elicited in a typical Nav1.8-null DRG neuron expressing Nav1.6r channels by a 500-ms ramp depolarization from -100 to +30 mV The peak sodium current amplitude elicited in this cell with step depolarizations was 65.1 nA. (From Herzog et al., 2003.)

VII. Dysregulated Sodium Channel Expression and Altered Activity Patterns: Lessons from Nerve Injury

As described later, there is also evidence for dysregulated neuronal sodium channel expression that can result in distorted firing patterns, both in animal models of MS and in MS. Precedent for a role of aberrantly expressed sodium channels in distorting the pattern of neuronal activity is provided by peripheral nerve disorders, another class of disorders involving pathology of axons. A growing body of evidence from animal models and humans indicates that changes in sodium channel transcription occur and contribute to changes in neuronal firing patterns that produce clinically significant phenomena, including paresthesia and neuropathic pain, in peripheral nerve injury and in peripheral neuropathies. The changes triggered by nerve injury within dorsal root ganglion (DRG) neurons include down-regulated expression of some sodium channels (Nav1.8 and Nav1.9) together with upregulated expression of another (Nav1.3) sodium channel (Dib-Hajj et al., 1996; Sleeper et aL, 2000; Waxman et al., 1994). Newly formed Nav1.3 mRNA is translated and produces Nav1.3 sodium channel protein that is transported to distal parts of transected axons, which are sites of abnormal impulse generation within neuromas (Black et al., 1999a). The aberrantly expressed Nav1.3 channels produce a rapidly repriming sodium current (i.e., a current with rapid recovery from inactivation) and this, in turn, leads to a decrease in the refractory period that contributes to ectopic activity of DRG neurons that underlies pain and paresthesia after nerve injury (Cummins and Waxman, 1997; Cummins et al., 2001; Dib-Hajj et al., 1999).

The factor(s) that triggers changes in sodium channel expression after nerve injury includes loss of access to peripheral pools of neurotrophic factors such as NGF and GDNF. Experimental delivery of NGF (Dib-Hajj et al., 1998a) and GDNF (Cummins et al., 2000) to peripherally axotomized DRG neurons reestablishes access to these factors and upregulates the levels of Nav1.8 and Nav1.9 mRNA and protein as well as the number of functional channels within the cell membrane (Cummins et al., 2000). These neurotrophic factors also down-regulate Nav1.3 expression in DRG neurons (Black et al., 1997; Boucher et al., 2000; Leffler et al., 2002).

Recent studies have also demonstrated upregulation of Nav1.3 within secondary and tertiary sensory neurons within the spinal cord afternerve injury (Hains et al., 2004). The increase in Nav1.3 occurs with a time course that parallels the onset of a pain syndrome and the development of hyperexcitability in these neurons. Antisense knockdown of Nav1.3 results in attenuation of this hyper-excitability and amelioration of pain-associated behaviors after spinal cord injury (Hains et al., 2004). Thus, axonal injury can trigger changes in the expression of sodium channels and resultant changes in excitability, within central neurons as well as DRG neurons; and these changes in excitability can produce clinical symptoms. In the next section, we describe altered expression of the Nav1.8 sodium channel in MS.

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